US20040157773A1

US20040157773A1 - Farnesyl protein transferase inhibitors for treating cachexia

Info

Publication number: US20040157773A1
Application number: US10/480,171
Authority: US
Inventors: David End
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2001-04-25
Filing date: 2002-04-17
Publication date: 2004-08-12
Also published as: JP2004526776A; WO2002085364A1; EP1390033A1

Abstract

The present invention relates to the use of farnesyl protein transferase inhibitors for the manufacture of a medicament for the treatment of cachexia.

Description

The present invention relates to the use of farnesyl protein transferase inhibitors for treating cachexia.

Greater than 50% of cancer patients experience cachexia, a syndrome of weight loss and wasting which compromises quality of life and contributes to mortality. Further symptoms include anorexia, chronic nausea, asthenia and change in body image. Moreover there is evidence that cachetic cancer patients have reduced survival as compared to non-cachetic patients with comparable disease extension. The weight loss reflects an activation of host catabolism with loss of muscle protein mass and body fat. The catabolism is activated by tumor-secreted and host immune cytokine release with IL-6, TNF-∝ and interferon-γ thought to play a prominent role. Corticosteroids and progestational drugs have been employed to treat cachexia and have been shown to improve appetite, food intake and the sensation of well-being and which elicit body weight gain. A new group of drugs, such as thalidomide and melatonin, because of their effect on tumor necrosis factor-α, and β2-adrenoceptor agonists because of their effects on muscle metabolism, and other agents, have also been suggested. However there is still a need for new treatments of cachexia as the above therapies have not always proved to be effective in the clinic.

It is an object of the present invention to provide a new method for the treatment of cachexia.

WO-97/21701 describes the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulae (I), (II) and (III), as well as intermediates of formula (II) and (III) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (III) are represented by

the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

R ¹is hydrogen, C_1-12alkyl, Ar¹, Ar²C_1-6alkyl, quinolinylC_1-6alkyl, pyridylC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, aminoC_1-6alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹or -Alk¹-S(O)₂—R⁹, wherein Alk¹is C_1-6alkanediyl,

R ⁹is hydroxy, C_1-6alkyl, C_1-6alkyloxy, amino, C_1-8alkylamino or C_1-8alkylamino substituted with C_1-6alkyloxycarbonyl;

R ², R³and R¹⁶each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar²C_1-6alkyl, Ar²oxy, Ar²C_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R²and R³taken together may form a bivalent radical of formula

—O—CH₂—O— (a-1),

—O—CH₂—CH₂—O— (a-2),

—O—CH═CH— (a-3),

—O—CH₂—CH₂— (a-4),

—O—CH₂—CH₂—CH₂— (a-5), or

—CH═CH—CH═CH— (a-6);

R ⁴and R⁵each independently are hydrogen, halo, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;

R ⁶and R⁷each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar²oxy, trihalomethyl, C_1-6alkylthio, di(C_1-6alkyl)amino, or when on adjacent positions R⁶and R⁷taken together may form a bivalent radical of formula

—O—CH₂—O— (c-1), or

—CH═CH—CH═CH— (c-2);

R ⁸is hydrogen, C_1-6alkyl, cyano, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylcarbonylC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, carboxyC_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono- or di(C_1-6alkyl)-aminoC_1-6alkyl, imidazolyl, haloC_1-6alkyl,

C _1-6alkyloxyC_1-6alkyl, aminocarbonylC_1-6alkyl, or a radical of formula

—O—R¹⁰ (b-1),

—S—R¹⁰ (b-2),

—N—R¹¹R¹² (b-3),

wherein R ¹⁰is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹, Ar²C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical or formula -Alk²-OR¹³or -Alk²-NR¹⁴R¹⁵;

R ¹¹is hydrogen, C_1-12alkyl, Ar¹or Ar²C_1-6alkyl;

R ¹²is hydrogen, C_1-6alkyl, C_1-16alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar¹, Ar²C_1-6alkyl, C_1-6alkylcarbonylC_1-6alkyl, a natural amino acid, Ar¹carbonyl, Ar²C_1-6alkylcarbonyl, aminocarbonylcarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino, or a radical or formula -Alk²-OR¹³or -Alk²-NR¹⁴R¹⁵;

wherein Alk ²is C_1-6alkanediyl;

R ¹³is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Ar¹or Ar²C_1-6alkyl;

R ¹⁴is hydrogen, C_1-6alkyl, Ar¹or Ar²C_1-6alkyl;

R ¹⁵is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹or Ar²C_1-6alkyl;

R ¹⁷is hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxycarbonyl, Ar¹;

R ¹⁸is hydrogen, C_1-6alkyl, C_1-6alkyloxy or halo;

R ¹⁹is hydrogen or C_1-6alkyl;

Ar ¹is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo; and

Ar ²is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo.

WO-97/16443 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by

the dotted line represents an optional bond;

X is oxygen or sulfur;

R ¹is hydrogen, C_1-12alkyl, Ar¹, Ar²C_1-6alkyl, quinolinylC_1-6alkyl, pyridyl-C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)-aminoC_1-6alkyl, aminoC_1-6alkyl,

or a radical of formula -Alk ¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹or -Alk¹-S(O)₂—R⁹, wherein Alk¹is C_1-6alkanediyl,

R ²and R³each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, amino-C_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar²C_1-6alkyl, Ar²oxy, Ar²C_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl; or

when on adjacent positions R ²and R³taken together may form a bivalent radical of formula

—O—CH₂—O— (a-1),

—O—CH₂—CH₂—O— (a-2),

—O—CH═CH— (a-3),

—O—CH₂—CH₂— (a-4),

—O—CH₂—CH₂—CH₂— (a-5), or

—CH═CH—CH═CH— (a-6);

R ⁴and R⁵each independently are hydrogen, Ar¹, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;

R ⁶and R⁷each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy or Ar²oxy;

R ⁸is hydrogen, C_1-6alkyl, cyano, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkyl-carbonylC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, hydroxycarbonylC_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, aminocarbonylC_1-6alkyl, Ar¹, Ar²C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl;

R ¹⁰is hydrogen, C_1-6alkyl, C_1-6alkyloxy or halo;

R ¹¹is hydrogen or C_1-6alkyl;

Ar ¹is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo;

WO-98/40383, concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII)

the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

-A- is a bivalent radical of formula

—CH═CH— (a-1),

—CH₂—CH₂— (a-2),

—CH₂—CH₂—CH₂— (a-3),

—CH₂—O— (a-4),

—CH₂—CH₂—O— (a-5),

—CH₂—S— (a-6),

—CH₂—CH₂—S— (a-7),

—CH═N— (a-8),

—N═N— (a-9), or

—CO—NH— (a-10);

wherein optionally one hydrogen atom may be replaced by C _1-4alkyl or Ar¹;

R ¹and R²each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar², Ar²—C_1-6alkyl, Ar²-oxy, Ar²—C_1-6alkyloxy; or when on adjacent positions R¹and R²taken together may form a bivalent radical of formula

—O—CH₂—O— (b-1),

—O—CH₂—CH₂—O— (b-2),

—O—CH═CH— (b-3),

—O—CH₂—CH₂— (b-4),

—O—CH₂—CH₂—CH₂— (b-5), or

—CH═CH—CH═CH— (b-6);

R ³and R⁴each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar³-oxy, C_1-6alkylthio, di(C_1-6alkyl)amino, trihalomethyl, trihalomethoxy, or

when on adjacent positions R ³and R⁴taken together may form a bivalent radical of formula

—O—CH₂—O— (c-1),

—O—CH₂—CH₂—O— (c-2), or

—CH═CH—CH═CH— (c-3);

R ⁵is a radical of formula

wherein R ¹³is hydrogen, halo, Ar⁴, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxy-C_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, C_1-6alkyloxy-carbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl; R¹⁴is hydrogen, C_1-6alkyl or di(C_1-4alkyl)aminosulfonyl;

R ⁶is hydrogen, hydroxy, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, C_1-6alkyloxycarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, Ar⁵, Ar⁵—C_1-6alkyloxyC_1-6alkyl; or a radical of formula

—O—R⁷ (e-1),

—S—R⁷ (e-2),

—N—R⁸R⁹ (e-3),

wherein R ⁷is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar⁶, Ar⁶—C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹⁰or -Alk-NR¹¹R¹²;

R ⁸is hydrogen, C_1-6alkyl, Ar⁷or Ar⁷—C_1-6alkyl;

R ⁹is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar⁸, Ar⁸—C_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, Ar⁸-carbonyl, Ar⁸—C_1-6alkylcarbonyl, aminocarbonylcarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino, or a radical or formula -Alk-OR¹⁰or -Alk-NR¹¹R¹²;

wherein Alk is C _1-6alkanediyl;

R ¹⁰is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Ar⁹or Ar⁹—C_1-6alkyl; R¹¹is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹⁰or Ar¹⁰—C_1-6alkyl; R¹²is hydrogen, C_1-6alkyl, Ar¹¹or Ar¹¹—C_1-6alkyl; and

Ar ¹to Ar¹¹are each independently selected from phenyl; or phenyl substituted with halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.

WO-98/49157, concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VIII)

the dotted line represents an optional bond;

X is oxygen or sulfur;

R ¹and R²each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar¹C_1-6alkyl, Ar¹oxy or Ar¹C_1-6alkyloxy;

R ³and R⁴each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar¹oxy, C_1-6alkylthio, di(C_1-6alkyl)amino, trihalomethyl or trihalomethoxy;

R ⁵is hydrogen, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, C_1-6alkyloxycarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, Ar¹, Ar¹C_1-6alkyloxyC_1-6alkyl; or a radical of formula

—O—R¹⁰ (a-1),

—S—R¹⁰ (a-2),

—N—R¹¹R¹² (a-3),

wherein R ¹⁰is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹, Ar¹C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵;

R ¹¹is hydrogen, C_1-6alkyl, Ar¹or Ar¹C_1-6alkyl;

R ¹²is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar¹, Ar¹C_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, Ar¹carbonyl, Ar¹C_1-6alkylcarbonyl, aminocarbonylcarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino, or a radical or formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵; wherein Alk is C_1-6alkanediyl;

R ¹³is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Ar¹or Ar¹C_1-6alkyl;

R ¹⁴is hydrogen, C_1-6alkyl, Ar¹or Ar¹C_1-6alkyl;

R ¹⁵is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹or Ar¹C_1-6alkyl;

R ⁶is a radical of formula

wherein R ¹⁶is hydrogen, halo, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxy-C_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, C_1-6alkyloxycarbonyl, C_1-6alkylthioC_1-6alkyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;

R ¹⁷is hydrogen, C_1-6alkyl or di(C_1-4alkyl)aminosulfonyl;

R ⁷is hydrogen or C_1-6alkyl provided that the dotted line does not represent a bond;

R ⁸is hydrogen, C_1-6alkyl or Ar²CH₂or Het¹CH₂;

R ⁹is hydrogen, C_1-6alkyl , C_1-6alkyloxy or halo; or

R ⁸and R⁹taken together to form a bivalent radical of formula

—CH═CH— (c-1),

—CH₂—CH₂— (c-2),

—CH₂—CH₂—CH₂— (c-3),

—CH₂—O— (c-4), or

—CH₂—CH₂—O— (c-5);

Ar ¹is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl;

Ar ²is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl; and

Het ¹is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.

As used in the foregoing definitions and hereinafter for compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) halo defines fluoro, chloro, bromo and iodo; C _1-6alkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; C_1-8alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C_1-6alkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; C_1-12alkyl again encompasses C_1-8alkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl; C_1-16alkyl again encompasses

C _1-12alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentedecyl and hexadecyl; C_2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C_1-6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof. The term “C(═O)” refers to a carbonyl group, “S(O)” refers to a sulfoxide and “S(O)₂” to a sulfon. The term “natural amino acid” refers to a natural amino acid that is bound via a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of the amino acid and the amino group of the remainder of the molecule. Examples of natural amino acids are glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine.

WO-00/39082 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IX)

or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein

═X ¹—X²—X³— is a trivalent radical of formula

═N—CR═CR⁷— (x-1),

═N—N═CR⁶— (x-2),

═N—NH—C(═O)— (x-3),

═N—N═N— (x-4),

═N—CR⁶═N— (x-5),

═CR⁶—CR⁷═CR⁸— (x-6),

═CR⁶—N═CR⁷— (x-7),

═CR⁶—NH—C(═O)— (x-8), or

═CR⁶—N═N— (x-9),

wherein each R ⁶, R⁷and R⁸are independently hydrogen, C_1-4alkyl, hydroxy, C_1-4alkyloxy, aryloxy, C_1-4alkyloxycarbonyl, hydroxyC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, cyano, amino, thio, C_1-4alkylthio, arylthio or aryl;

>Y ¹—Y²— is a trivalent radical of formula

>CH—CHR⁹— (y-1),

>C═N— (y-2),

>CH—NR⁹— (y-3),or

>C═CR⁹— (y-4);

wherein each R ⁹independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC_1-4alkyl, cyano, carboxyl, C_1-4alkyl, C_1-4alkyloxy, C_1-4alkyloxyC_1-4alkyl, C_1-4alkyloxycarbonyl, mono- or di(C_1-4alkyl)amino, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, aryl;

r and s are each independently 0, 1, 2, 3, 4 or 5;

t is 0, 1, 2 or 3;

each R ¹and R²are independently hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkylthio, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)amino, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, aryl, arylC_1-6alkyl, aryloxy or arylC_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, aminocarbonyl, aminoC_1-6alkyl, mono- or di(C_1-6alkyl)aminocarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl; or

two R ¹or R²substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula

—O—CH₂—O— (a-1),

—O—CH₂—CH₂—O— (a-2),

—O═CH═CH— (a-3),

—O—CH₂—CH₂— (a-4),

—O—CH₂—CH₂—CH₂— (a-5), or

—CH═CH—CH═CH— (a-6);

R ³is hydrogen, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, hydroxycarbonyl, hydroxycarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, C_1-6alkylcarbonylC_1-6alkyl, C_1-6alkyloxycarbonyl, aryl,

arylC _1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl;

or a radical of formula

—O—R¹⁰ (b-1)

—S—R¹⁰ (b-2),

—NR¹¹R¹² (b-3),

wherein R ¹⁰is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, aryl, arylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵;

R ¹¹is hydrogen, C_1-6alkyl, aryl or arylC_1-6alkyl;

R ¹²is hydrogen, C_1-6alkyl, aryl, hydroxy, amino, C_1-6alkyloxy, C_1-6alkylcarbonylC_1-6alkyl, arylC_1-6alkyl, C_1-6alkylcarbonylamino, mono- or di(C_1-6alkyl)amino, C_1-6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloC_1-6alkylcarbonyl, arylC_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, mono- or di(C_1-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C_1-3alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, or a radical or formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵;

wherein Alk is C _1-6alkanediyl;

R ¹³is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxyC_1-6alkyl, aryl or arylC_1-6alkyl;

R ¹⁴is hydrogen, C_1-6alkyl, aryl or arylC_1-6alkyl;

R ¹⁵is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, aryl or arylC_1-6alkyl;

R ⁴is a radical of formula

wherein R ¹⁶is hydrogen, halo, aryl, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, mono- or di(C_1-4alkyl)amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylthioC_1-6alkyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl; R¹⁶may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R¹⁶when bound to the nitrogen is limited to hydrogen, aryl, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl; R¹⁷is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, arylC_1-6alkyl, trifluoromethyl or di(C_1-4alkyl)aminosulfonyl;

R ⁵is C_1-6alkyl, C_1-6alkyloxy or halo;

aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C _1-6alkyl, C_1-6alkyloxy or trifluoromethyl.

WO-01/98302 concerns the (−) enantiomer of a racemic compound identified in the above-mentioned WO-00/39082, namely 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine and its pharmaceutically acceptable addition salts.

As used in the foregoing definitions and hereinafter for compounds of formula (IX), halo is generic to fluoro, chloro, bromo and iodo; C _1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C_1-6alkyl includes C_1-4alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methyl-butyl, hexyl, 2-methylpentyl and the like; C_1-6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; C_2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like. The term “S(O)” refers to a sulfoxide and “S(O)₂” to a sulfon.

Other useful farnesyl protein transferase inhibitors include Arglabin (i.e. 1(R)-10-epoxy-5(S),7(S)-guaia-3(4),11(13)-dien-6,12-olide descibed in WO-98/28303 (NuOncology Labs); perrilyl alcohol described in WO-99/45912 (Wisconsin Genetics); SCH-66336, i.e. (+)-(R)-4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide, described in U.S. Pat. No. 5874442 (Schering); L778123, i.e. 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, described in WO-00/01691 (Merck); compound 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone described in WO-94/10138 (Merck); and BMS 214662, i.e. (R)-2,3,4,5-tetrahydro-1-(IH-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulphonyl)-1H-1,4-benzodiazapine-7-carbonitrile, described in WO 97/30992 (Bristol Myers Squibb) and Pfizer compounds (A) and (B) described in WO-00/12498 and WO-00/12499:

Unexpectedly, we have now found that farnesyl protein transferase inhibitors, including those identified supra, which may hereinafter be referred to as compounds according to the present invention, are useful for the treatment of cachexia.

Accordingly, the present invention relates to the use of a farnesyl protein transferase inhibitor in the manufacture of a medicament for the treatment of cachexia.

Examples of farnesyl transferase inhibitors which may be used in accordance with the invention are those compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX), particularly compounds of formula (I), including related compounds of formula (II) and (III), and compounds of formula (IX).

A further feature of the present invention includes the use of Arglabin, perrilyl alcohol, SCH-66336, 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone (Merck); L778123, BMS 214662, Pfizer compounds A and B, in the manufacture of a medicament for the treatment of cachexia.

The invention further includes a method of treatment of cachexia in a mammal, including a human, by administering a therapeutically effective amount of a compound according to the present invention.

With regard to the compounds of formula (I), (II) and (III) above, R ⁴or R⁵may also be bound to one of the nitrogen atoms in the imidazole ring. In that case the hydrogen on the nitrogen is replaced by R⁴or R⁵and the meaning of R⁴and R⁵when bound to the nitrogen is limited to hydrogen, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl, C_1-6alkylS(O)₂C_1-6alkyl.

Preferably the substituent R ¹⁸is situated on the 5 or 7 position of the quinolinone moiety and substituent R¹⁹is situated on the 8 position when R¹⁸is on the 7-position.

Interesting compounds are these compounds of formula (I) wherein X is oxygen.

Also interesting compounds are these compounds of formula (I) wherein the dotted line represents a bond, so as to form a double bond.

Another group of interesting compounds are those compounds of formula (I) wherein R ¹is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, wherein Alk¹is methylene and R⁹is C_1-8alkyl-amino substituted with C_1-6alkyloxycarbonyl.

Still another group of interesting compounds are those compounds of formula (I) wherein R ³is hydrogen or halo; and R²is halo, C_1-6alkyl, C_2-6alkenyl, C_1-6alkyloxy, trihalomethoxy or hydroxyC_1-6alkyloxy.

A further group of interesting compounds are those compounds of formula (I) wherein R ²and R³are on adjacent positions and taken together to form a bivalent radical of formula (a-1), (a-2) or (a-3).

A still further group of interesting compounds are those compounds of formula (I) wherein R ⁵is hydrogen and R⁴is hydrogen or C_1-6alkyl.

Yet another group of interesting compounds are those compounds of formula (I) wherein R ⁷is hydrogen; and R⁶is C_1-6alkyl or halo, preferably chloro, especially 4-chloro.

A particular group of compounds are those compounds of formula (I) wherein R ⁸is hydrogen, hydroxy, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxy-carbonylC_1-6alkyl, imidazolyl, or a radical of formula —NR¹¹R¹²wherein R¹¹is hydrogen or C_1-12alkyl and R¹²is hydrogen, C_1-6alkyl, C_1-6alkyloxy, hydroxy, C_1-6alkyloxyC_1-6alkylcarbonyl, or a radical of formula -Alk²-OR¹³wherein R¹³is hydrogen or C_1-6alkyl.

Preferred compounds are those compounds wherein R ¹is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, wherein Alk¹is methylene and R⁹is C_1-8alkylamino substituted with C_1-6alkyloxycarbonyl; R²is halo, C_1-6alkyl, C_2-6alkenyl, C_1-6alkyloxy, trihalomethoxy, hydroxyC_1-6alkyloxy or Ar¹; R³is hydrogen; R⁴is methyl bound to the nitrogen in 3-position of the imidazole; R⁵is hydrogen; R⁶is chloro; R⁷is hydrogen; R⁸is hydrogen, hydroxy, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, imidazolyl, or a radical of formula —NR¹¹R¹²wherein R¹¹is hydrogen or C_1-12alkyl and R¹²is hydrogen, C_1-6alkyl, C_1-6alkyloxy, C_1-6alkyloxyC_1-6alkylcarbonyl, or a radical of formula -Alk²-OR¹³wherein R¹³is C_1-6alkyl; R¹⁷is hydrogen and R¹⁸is hydrogen.

Most preferred compounds are

4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,

6-[amino(4-chlorophenyl)-1-methyl-1-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;

6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;

6-[(4-chlorophenyl)(1-methyl-1-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone monohydrochloride.monohydrate;

6-[amino(4-chlorophenyl)(1-methyl-1-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,

6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt; and

(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;

or a pharmaceutically acceptable acid addition salt thereof. The latter compound is especially preferred.

Further preferred embodiments of the present invention include the use of compounds of formula (IX) wherein one or more of the following restrictions apply:

═X ¹—X²—X3 is a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9) wherein each R⁶independently is hydrogen, C_1-4alkyl, C_1-4alkyloxycarbonyl, amino or aryl and R⁷is hydrogen;

>Y ¹—Y²— is a trivalent radical of formula (y-1), (y-2), (y-3), or (y-4) wherein each R⁹independently is hydrogen, halo, carboxyl, C_1-4alkyl or C_1-4alkyloxycarbonyl;

r is 0, 1 or 2;

s is 0 or 1;

t is 0;

R ¹is halo, C_1-6alkyl or two R¹substituents ortho to one another on the phenyl ring may independently form together a bivalent radical of formula (a-1);

R ²is halo;

R ³is halo or a radical of formula (b-1) or (b-3) wherein

R ¹⁰is hydrogen or a radical of formula -Alk-OR³.

R ¹¹is hydrogen;

R ¹²is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy or mono- or

di(C _1-6alkyl)aminoC_1-6alkylcarbonyl;

Alk is C _1-6alkanediyl and R¹³is hydrogen;

R ⁴is a radical of formula (c-1) or (c-2) wherein

R ¹⁶is hydrogen, halo or mono-or di(C_1-4alkyl)amino;

R ¹⁷is hydrogen or C_1-6alkyl;

aryl is phenyl.

A particular group of compounds consists of those compounds of formula (IX) wherein ═X ¹—X²—X³is a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r is 0 or 1, s is 1, t is 0, R¹is halo, C_(1-4)alkyl or forms a bivalent radical of formula (a-1), R²is halo or C_1-4alkyl, R³is hydrogen or a radical of formula (b-1) or (b-3), R⁴is a radical of formula (c-1) or (c-2), R⁶is hydrogen, C_1-4alkyl or phenyl, R⁷is hydrogen, R⁹is hydrogen or C_1-4alkyl, R¹⁰is hydrogen or -Alk-OR¹³, R¹¹is hydrogen and R¹²is hydrogen or C_1-6alkylcarbonyl and R¹³is hydrogen;

Preferred compounds are those compounds of formula (IX) wherein ═X ¹—X²—X³is a trivalent radical of formula (x-1) or (x-4), >Y1-Y2 is a trivalent radical of formula (y-4), r is 0 or 1, s is 1, t is 0, R¹is halo, preferably chloro and most preferably 3-chloro, R²is halo, preferably 4-chloro or 4-fluoro, R³is hydrogen or a radical of formula (b-1) or (b-3), R⁴is a radical of formula (c-1) or (c-2), R⁶is hydrogen, R⁷is hydrogen, R⁹is hydrogen, R¹⁰is hydrogen, R¹¹is hydrogen and R¹²is hydrogen;

Other preferred compounds are those compounds of formula (IX) wherein ═X ¹—X²—X³is a trivalent radical of formula (x-2), (x-3) or (x-4), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R¹is halo, preferably chloro, and most preferably 3-chloro or R¹is C_1-4alkyl, preferably 3-methyl, R²is halo, preferably chloro, and most preferably 4-chloro, R³is a radical of formula (b-1) or (b-3), R⁴is a radical of formula (c-2), R⁶is C_1-4alkyl, R⁹is hydrogen, R¹⁰and R¹¹are hydrogen and R¹²is hydrogen or hydroxy;

The most preferred compounds of formula (IX) are

7-[(4-fluorophenyl)(1-imidazol-1-yl)methyl]-5-phenylimidazo[1,2-a]quinoline;

α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo[1,2-a]quinoline-7-methanol;

5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-imidazo[1,2-a]quinoline-7-methanol;

5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-a]quinoline-7-methanamine;

5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;

5-(3-chlorophenyl)-α-(4-chlorophenyl)-1-methyl-α-(1-methyl-1H-imidazol-5-yl)-1,2,4-tetrazolo-4,3-a]quinoline-7-methanol;

5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-α-(1-methyl-1-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;

5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine;

5-(3-chlorophenyl)-α-(4-chlorophenyl)-N-hydroxy-α-(1-methyl-1H-imidazol-5-yl)tetrahydro[1,5-a]quinoline-7-methanamine;

α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo[1,5-a]quinoline-7-methanamine; the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof.

5-(3-Chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine, especially the (−) enantiomer, and its pharmaceutically acceptable addition salts are particularly preferred.

The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) are able to form. The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

The terms acid or base addition salt also comprise the hydrates and the solvent addition forms which the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms of compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formulae (I), (I1), (III), (IV), (V), (VI), (VII), (VIII) and (IX) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formulae (I), (ID), (III), (IV), (V), (VI), (VII), (VIII) and (IX) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

Some of the compounds of formulae (I), (ID), (III), (IV), (V), (VI), (VII), (VIII) and (IX) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX)” is meant to include also the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms.

Other farnesyl protein transferase inhibitors which can be employed in accordance with the present include Arglabin, perrilyl alcohol, SCH-66336, 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone (Merck); L778123, BMS 214662, Pfizer compounds A and B described above. These compounds can be prepared, for example, by methods described in the relevant patent specifications identified above which are incorporated herein by reference.

Farnesyl protein transferase inhibitors can be prepared and formulated into pharmaceutical compositions by methods known in the art and in particular according to the methods described in the published patent specifications mentioned herein and incorporated by reference ; for the compounds of formulae (I), (II) and (III) suitable examples can be found in WO-97/21701. Compounds of formulae (IV), (V), and (VI) can be prepared and formulated using methods described in WO 97/16443, compounds of formulae (VII) and (VIII) according to methods described in WO 98/40383 and WO 98/49157 and compounds of formula (IX) according to methods described in WO 00/39082 respectively. To prepare the aforementioned medicaments, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.

These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, rectal, percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.

For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.

For rectal administration, the pharmaceutical compositions may be presented as suppositories or as enemas. For rectal administration wherein the carrier is a solid, unit dose suppositories are preferred. Suitable carriers include cocoa butter and other materials commonly used in the art.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

Preferably, a therapeutic effective amount of the medicament comprising a compound according to the present invention is administered orally or parenterally. Said therapeutically effective amount is the amount that is effective in treating cachexia. The amount of compound according to the present invention, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, route of administration, the age and condition of the recipient, and the particular disorder being treated.

On the basis of the current data, it appears that a pharmaceutical composition comprising a compound of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) and in particular (+)-6-[amino(4-chlorophenyl) (1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone or 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine, especially the (−) enantiomer, as the active ingredient can be administered orally in an amount of from 10 to 1500 mg daily, either as a single dose or subdivided into more than one dose. A preferred amount ranges from 100 to 1,000 mg daily, including 50 to 1,000 mg daily. A particularly preferred dosage for such a compound is 300mg administered twice daily. This treatment can be given either continuously or intermittently in cycles of 3-4 weeks with treatment given for 1-21 days per cycle.

Suitable dosages for the compounds Arglabin (WO98/28303), perrilyl alcohol (WO 99/45712), SCH-66336 (U.S. Pat. No. 5,874,442), L778123 (WO 00/01691), 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone (WO94/10138), BMS 214662 (WO 97/30992), Pfizer compounds A and B (WO 00/12499 and WO 00/12498) are given in the aforementioned patent specifications which are incorporated herein by reference or are known to or can be readily determined by a person skilled in the art.

The following study showing the anticachexia effect of a farnesyl protein transferase inhibitor illustrates the present invention The farnesyl protein transferase inhibitor studied is (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, which is identified in the study as R115777.

MATERIALS AND METHODS

Cell Culture [0188]
A375.S2 human melanoma cells were purchased from the American Type Culture Collection (Rockville, Md.). Cells were maintained in Dulbecco's Modified Eagle's Medium supplemented with pyruvate, nonessential amino acids, 10% fetal calf serum and penicillin-streptomycin. [0189]
Animals [0190]
Female nu/nu immunodeficient nude mice (42 days old) were purchased from Charles River Laboratories (Wilmington, Mass.). Mice were housed five per cage in microisolator cages placed in laminar flow shelving to maintain sterility. All bedding, food, water and cages were autoclaved. Animals were handled within the sterile confines of a laminar flow cabinet. The mice were otherwise maintained under standard vivarium conditions. [0191]
Tumor Studies in Nude Mice [0192]
Cells growing as monolayers in T150 tissue culture flasks were detached by trypsinization with 10 ml of 0.05% trypsin plus 0.53 mM EDTA per flask. Tumor cell suspensions were pooled and trypsin was inactivated by the addition of serum containing medium (10 ml per 40 ml of trypsin cell suspension). Cells were collected by centrifugation and resuspended in Hank's Balanced Salt Solution (HBSS) warmed to 37° C. A 1.0 ml portion of cell suspension was added to 20 ml of diluent and counted on a Coulter particle counter. The cell suspensions were recentrifuged and resuspended at a concentration of 1×10[0193] ⁶cell per 0.10 ml of HBSS. Mice were inoculated with a single subcutaneous injection of 0.10 ml of tumor cell suspension in the inguinal region. Mice were housed five per cage with 15 mice assigned to each treatment group. Mice were tagged by ear punches to allow the monitoring of individual mice during the course of the study. Body weight and tumor size determined from caliper measurements were measured weekly. The caliper measurements of length and width were multiplied to obtain tumor areas. At the end of study, mice were sacrificed by CO₂asphyxiation. Three days after tumor inoculation, the five-day treatment with R115777 was initiated. R115777 was administered once daily by oral gavage in a 20% β-cyclodextrin vehicle as a volume of 0.10 ml of solution per 10 gm body weight. Control groups received the same dosage volume of the 20% β-cyclodextrin vehicle.
Compounds [0194]
R115777 was prepared for oral administration by dissolving the compound first as a 2× concentrated stock in 40% hydroxypropyl β-cyclodextrin in 0.1 N HCl. R115777 was dissolved by stirring vigorously approximately 30 minutes followed by sonication for 10 min. The R115777 solutions were brought to a final concentration by diluting 1:1 with 0.1 N HCl. The final drug solutions were sterile filtered immediately and transferred to sterile tubes. Solutions were stored refrigerated and protected from light during the course of the study and sterility was maintained by opening solutions under sterile laminar flow conditions. [0195]
Data Analysis [0196]
Analysis of variance, mean values for treatment groups and standard error of the mean for in vivo parameters were calculated using IMSL subroutines on a VAX computer. A value of p<0.05 was considered significant. Weight loss was calculated for each individual animal from [0197] day 1 to day 23. Mean body weight loss for each treatment group was calculated and used for statistical analyses.
Results [0198]
Following subcutaneous implantation of 2×10[0199] ⁶A375.S2 tumor cells, a lag period of 14 days preceded the appearance of measurable tumors. Thereafter, a rapid growth of tumors was observed from day 15 to 21 (FIG. 1). Administration of R115777 produced a minimal reduction in tumor growth as determined from the biweekly tumor area measurements. With the onset of tumor growth at day 14, the vehicle-treated animals presented with a severe weight loss (FIG. 2). The study was stopped on day 23 because of the mortality and severe weight loss observed in vehicle-treated animals. Treatment with R115777 appeared to prevent or delay the weight loss in a dose-dependent fashion. When the weight loss data for each individual animal from day 1 to day 23 was analysed and corrected for the weight contribution of the tumor burden, a significant dose dependent reduction of body weight loss was observed in mice treated with R115777 (FIG. 3). Vehicle-treated animals lost approximately 7 g or approximately 30% of the starting body weight. Daily oral treatment with R115777 prevented the weight loss with 28%, 45% and 67% reductions in weight loss at the respective doses of at doses of 50, 100 and 200 mg/kg. The effects of R115777 greatly exceeded the antitumoral effects of R115777 measured as either tumor area (FIG. 4) or postmortem tumor weight (FIG. 5). Only a 27% reduction of final tumor weight was observed at the highest tested dose in this study.

Claims

1. Use of a farnesyl protein transferase inhibitor in the manufacture of a medicament for the treatment of cachexia.

2. Use according to claim 1 in which the farnesyl transferase inhibitor is selected from the compounds of formulae I, II, III, IV, V, VI, VII, VIII and IX infra

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹is hydrogen, C_1-12alkyl, Ar¹, Ar²C_1-6alkyl, quinolinylC_1-6alkyl, pyridylC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, aminoC_1-6alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹or -Alk¹-S(O)₂—R⁹, wherein Alk¹is C_1-6alkanediyl,

R⁹is hydroxy, C_1-6alkyl, C_1-6alkyloxy, amino, C_1-8alkylamino or C_1-8alkylamino substituted with C_1-6alkyloxycarbonyl;

R², R³and R¹⁶each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar²C_1-6alkyl, Ar²oxy, Ar²C_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R²and R³taken together may form a bivalent radical of formula

—O—CH₂—O— (a-1), —O—CH₂—CH₂—O— (a-2), —O—CH═CH— (a-3), —O—CH₂—CH₂— (a-4), —O—CH₂—CH₂—CH₂— (a-5), or —CH═CH—CH═CH— (a-6);

R⁴and R⁵each independently are hydrogen, halo, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)2C_1-6alkyl;

R⁶and R⁷each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar²oxy, trihalomethyl, C_1-6alkylthio, di(C_1-6alkyl)amino, or when on adjacent positions R⁶and R⁷taken together may form a bivalent radical of formula

—O—CH₂—O— (c-1), or —CH═CH—CH═CH— (c-2);

R⁸is hydrogen, C_1-6alkyl, cyano, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylcarbonylC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, carboxyC_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, imidazolyl, haloC_1-6alkyl,

C_1-6alkyloxyC_1-6alkyl, aminocarbonylC_1-6alkyl, or a radical of formula

—O—R¹⁰ (b-1), —S—R¹⁰ (b-2), —N—R¹¹R¹² (b-3),

wherein R¹⁰is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹, Ar²C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical or formula -Alk²-OR¹³or -Alk²-NR¹⁴R¹⁵;

R¹¹is hydrogen, C_1-12alkyl, Ar¹or Ar²C_1-6alkyl;

R¹²is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar¹, Ar²C_1-6alkyl, C_1-6alkylcarbonylC_1-6alkyl, a natural amino acid, Ar¹carbonyl, Ar²C_1-6alkylcarbonyl, aminocarbonylcarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino, or a radical or formula-Alk²-OR¹³or -Alk²-NR¹⁴R¹⁵;

wherein Alk²is C_1-6alkanediyl;

R¹³is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Ar¹or Ar²C_1-6alkyl;

R¹⁴is hydrogen, C_1-6alkyl, Ar¹or Ar²C_1-6alkyl;

R¹⁵is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹or Ar²C_1-6alkyl;

R¹⁷is hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxycarbonyl, Ar¹;

R¹⁸is hydrogen, C_1-6alkyl, C_1-6alkyloxy or halo;

R¹⁹is hydrogen or C_1-6alkyl;

Ar¹is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo; and

Ar²is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo.

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹is hydrogen, C_1-12alkyl, Ar¹, Ar²C_1-6alkyl, quinolinylC_1-6alkyl, pyridyl-C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)-aminoC_1-6alkyl, aminoC_1-6alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹or -Alk¹-S(O)₂—R⁹,

wherein Alk¹is C_1-6alkanediyl,

R²and R³each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, amino-C_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar²C_1-6alkyl, Ar²oxy, Ar²C_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl; or when on adjacent positions R²and R³taken together may form a bivalent radical of formula

R⁴and R⁵each independently are hydrogen, Ar¹, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;

R⁶and R⁷each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy or Ar²oxy;

R⁸is hydrogen, C_1-6alkyl, cyano, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkyl-carbonylC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, hydroxycarbonylC_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, aminocarbonylC_1-6alkyl, Ar¹,

Ar²C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl;

R¹⁰is hydrogen, C_1-6alkyl, C_1-6alkyloxy or halo;

R¹¹is hydrogen or C_1-6alkyl;

Ar¹is phenyl or phenyl substituted with C_1-6alkyl,hydroxy,amino, C_1-6alkyloxy or halo;

the dotted line represents an optional bond;

X is oxygen or sulfur;

-A- is a bivalent radical of formula

—CH═CH— (a-1), —CH₂—CH₂— (a-2), —CH₂—CH₂—CH₂— (a-3), —CH₂—O— (a-4), —CH₂—CH₂—O— (a-5), —CH₂—S— (a-6), —CH₂—CH₂—S— (a-7), —CH═N— (a-8), —N═N— (a-9), or —CO—NH— (a-10);

wherein optionally one hydrogen atom may be replaced by C_1-4alkyl or Ar¹;

R¹and R²each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar², Ar²—C_1-6alkyl, Ar²-oxy, Ar²—C_1-6alkyloxy; or when on adjacent positions R¹and R²taken together may form a bivalent radical of formula

—O—CH₂—O— (b-1), —O—CH₂—CH₂—O— (b-2), —O—CH═CH— (b-3), —O—CH₂—CH₂— (b-4), —O—CH₂—CH₂—CH₂— (b-5), or —CH═CH—CH═CH— (b-6);

R³and R⁴each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar³-oxy, C_1-6alkylthio, di(C_1-6alkyl)amino, trihalomethyl, trihalomethoxy, or

when on adjacent positions R³and R⁴taken together may form a bivalent radical of formula

—O—CH₂—O— (c-13, —O—CH₂—CH₂—O— (c-2), or —CH═CH—CH═CH— (c-3);

R⁵is a radical of formula

wherein R¹³is hydrogen, halo, Ar⁴, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxy-C_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, C_1-6alkyloxy-carbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)²C_1-6alkyl;

R¹⁴is hydrogen, C_1-6alkyl or di(C_1-4alkyl)aminosulfonyl;

R⁶is hydrogen, hydroxy, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, C_1-6alkyloxycarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, Ar⁵, Ar⁵—C_1-6alkyloxyC_1-6alkyl; or a radical of formula

—O—R⁷ (e-1), —S—R⁷ (e-2), —N—R⁸R⁹ (e-3),

wherein R⁷is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar⁶, Ar⁶—C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹⁰or -Alk-NR¹¹R¹²;

R⁸is hydrogen, C_1-6alkyl, Ar⁷or Ar⁷—C_1-6alkyl;

R⁹is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar⁸, Ar⁸—C_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, Ar⁸-carbonyl, Ar⁸-C_1-6alkylcarbonyl, aminocarbonylcarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino, or a radical or formula -Alk-OR¹⁰or -Alk-NR¹¹R¹²;

wherein Alk is C_1-6alkanediyl;

R¹⁰is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Ar⁹or Ar⁹-C_1-6alkyl;

R¹¹is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹⁰or Ar¹⁰—C_1-6alkyl;

R¹²is hydrogen, C_1-6alkyl, Ar¹¹or Ar¹¹—C_1-6alkyl; and

Ar¹to Ar¹¹are each independently selected from phenyl; or phenyl substituted with halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹and R²each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar¹C_1-6alkyl, Ar¹oxy or Ar¹C_1-6alkyloxy;

R³and R⁴each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar¹oxy, C_1-6alkylthio, di(C_1-6alkyl)amino, trihalomethyl or trihalomethoxy;

R⁵is hydrogen, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, C_1-6alkyloxycarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, Ar¹, Ar¹C_1-6alkyloxyC_1-6alkyl; or a radical of formula

—O—R¹⁰ (a-1), —S—R¹⁰ (a-2), —N—R¹¹R¹² (a-3),

wherein R¹⁰is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹, Ar¹C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵;

R¹¹is hydrogen, C_1-6alkyl, Ar¹or Ar¹C_1-6alkyl;

R¹²is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar¹, Ar¹C_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, Ar¹carbonyl, Ar¹C_1-6alkylcarbonyl, aminocarbonylcarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino, or a radical or formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵; wherein Alk is C_1-6alkanediyl;

R¹³is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Ar¹or Ar¹C_1-6alkyl;

R¹⁴is hydrogen, C_1-6alkyl, Ar¹or Ar¹C_1-6alkyl;

R¹⁵is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹or Ar¹C_1-6alkyl;

R⁶is a radical of formula

wherein R¹⁶is hydrogen, halo, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxy-C_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, C_1-6alkyloxycarbonyl, C_1-6alkylthioC_1-6alkyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;

R¹⁷is hydrogen, C_1-6alkyl or di(C_1-4alkyl) aminosulfonyl;

R⁷is hydrogen or C_1-6alkyl provided that the dotted line does not represent a bond;

R⁸is hydrogen, C_1-6alkyl or Ar²CH₂or Het¹CH₂;

R⁹is hydrogen, C_1-6alkyl , C_1-6alkyloxy or halo; or

R⁸and R⁹taken together to form a bivalent radical of formula

—CH═CH— (c-1), —CH₂—CH₂— (c-2), —CH₂—CH₂—CH₂— (c-3), —CH₂—O— (c-4), or —CH₂—CH₂—O— (c-5);

Ar¹is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl;

Ar²is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl; and

Het¹is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl

and

═X¹—X²—X³— is a trivalent radical of formula

═N—CR⁶═CR⁷— (x-1), ═N—N═CR⁶— (x-2), ═N—NH—C(═O)— (x-3), ═N—N═N— (x-4), ═N—CR⁶═N— (x-5), ═CR⁶—CR⁷═CR⁸— (x-6), ═CR⁶—N═CR⁷— (x-7), ═CR⁶—NH—C(═O)— (x-8), or ═CR⁶—N═N— (x-9);

wherein each R⁶, R⁷and R⁸are independently hydrogen, C_1-4alkyl, hydroxy, C_1-4alkyloxy, aryloxy, C_1-4alkyloxycarbonyl, hydroxyC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, cyano, amino, thio, C_1-4alkylthio, arylthio or aryl;

>Y¹—Y²— is a trivalent radical of formula

>CH—CHR⁹— (y-1), >C═N— (y-2), >CH—NR⁹— (y-3), or >C═CR⁹— (y-4);

wherein each R⁹independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC_1-4alkyl, cyano, carboxyl, C_1-4alkyl, C_1-4alkyloxy, C_1-4alkyloxyC_1-4alkyl, C_1-4alkyloxycarbonyl, mono- or di(C_1-4alkyl)amino, mono- or di(C_1-4alkyl)aminoC_1-4alkyl, aryl;

r and s are each independently 0, 1, 2, 3, 4 or 5;

t is 0, 1, 2 or 3;

each R¹and R²are independently hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C₂-₆alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkylthio, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)amino, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, aryl, arylC_1-6alkyl, aryloxy or arylC_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, aminocarbonyl, aminoC_1-6alkyl, mono- or di(C_1-6alkyl)aminocarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl; or

two R¹or R²substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula

—O—CH₂—O— (a-1), —O—CH₂—CH₂—O— (a-2), —O═CH═CH— (a-3), —O—CH₂—CH₂— (a-4), —O—CH₂—CH₂—CH₂— (a-5), or —CH═CH—CH═CH— (a-6);

R³is hydrogen, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, hydroxycarbonyl, hydroxycarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, C_1-6alkylcarbonylC_1-6alkyl, C_1-6alkyloxycarbonyl, aryl, arylC_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl;

or a radical of formula

—O—R¹⁰ (b-1), —S—R¹⁰ (b-2), —NR¹¹R¹² (b-3),

wherein R¹⁰is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, aryl, arylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵;

R¹¹is hydrogen, C_1-6alkyl, aryl or arylC_1-6alkyl;

R¹²is hydrogen, C_1-6alkyl, aryl, hydroxy, amino, C_1-6alkyloxy, C_1-6alkylcarbonylC_1-6alkyl, arylC_1-6alkyl, C_1-6alkylcarbonylamino, mono- or di(C_1-6alkyl)amino, C_1-6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloC_1-6alkylcarbonyl, arylC_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, mono- or di(C_1-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C_1-3alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, or a radical or formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵;

wherein Alk is C_1-6alkanediyl;

R¹³is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxyC_1-6alkyl, aryl or arylC_1-6alkyl;

R¹⁴is hydrogen, C_1-6alkyl, aryl or arylC_1-6alkyl;

R¹⁵is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, aryl or arylC_1-6alkyl;

R⁴is a radical of formula

wherein R¹⁶is hydrogen, halo, aryl, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, mono- or di(C_1-4alkyl)amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylthioC_1-6alkyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl; R¹⁶may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R¹⁶when bound to the nitrogen is limited to hydrogen, aryl, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl; R¹⁷is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, arylC_1-6alkyl, trifluoromethyl or di(C_1-4alkyl)aminosulfonyl;

R⁵is C_1-6alkyl, C_1-6alkyloxy or halo;

aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.

3. Use according to claim 2 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein R⁸is hydrogen, hydroxy, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, imidazolyl, or a radical of formula —NR¹¹R¹²wherein R¹¹is hydrogen or C_1-12alkyl and R¹²is hydrogen, C_1-6alkyl, C_1-6alkyloxy, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, or a radical of formula -Alk²-OR¹³wherein R¹³is hydrogen or C_1-6alkyl.

4. Use according to claim 1 wherein the farnesyl protein transferase inhibitor is

4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1-imidazol-5-yl)-methyl]-1-methyl-2(1)-quinolinone,

6-[amino(4-chlorophenyl)-1-methyl-1-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2( 1)-quinolinone;

6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxy-phenyl)-1-methyl-2(1H)-quinolinone;

6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone monohydrochloride.monohydrate;

6-[amino(4-chlorophenyl)(1-methyl-1-imidazol-5-yl)methyl]-4-(3-ethoxy-phenyl)-1-methyl-2(1H)-quinolinone, and

6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a stereoisomeric form or a pharmaceutically acceptable acid or base addition salt thereof.

5. Use according to claim 1 wherein the farnesyl protein transferase inhibitor is (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

6. Use according to claim 1 wherein the farnesyl protein transferase inhibitor is a compound of formula (IX) wherein ═X¹—X²—X³is a trivalent radical of formula (x-2), (x-3) or (x-4), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R¹is halo, preferably chloro, and most preferably 3-chloro or R¹is C_1-4alkyl, preferably 3-methyl, R²is halo, preferably chloro, and most preferably 4-chloro, R³is a radical of formula (b-1) or (b-3), R⁴is a radical of formula (c-2), R⁶is C_1-4alkyl, R⁹is hydrogen, R¹⁰and R¹¹are hydrogen and R¹²is hydrogen or hydroxy.

7. Use according to claim 6 wherein the farnesyl protein transferase inhibitor is 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine or a pharmaceutically acceptable acid addition salt thereof.

8. Use according to any of claims 1 to 7 wherein the medicament is adapted for oral, rectal or parenteral administration.

9. A method of treating cachexia in a mammal comprising administering a therapeutically effective amount of a farnesyl protein transferase inhibitor described in any of claims 1 to 7 to said mammal.